STEMI: Timing to Reperfusion / Reperfusion Injury A Multi-Layer Challenge

to Decrease Infarct Size

Borja Ibanez, MD PhD FESC.

- Centro Nacional de Investigaciones

Cardiovasculares Carlos III (CNIC).

- Fundación Jiménez Díaz Hospital.

CONFLICTS OF INTEREST

B Ibanez has no conflicts to declare

1) Reperfusion: a paradigm shift from mortality to HF.

Index

2) Next goal: Infarct size limitation in reperfused STEMI.

3) Ischemia/Reperfusion injury.

4) Therapies to reduce infarct size:

Reperfusion

+ Conditioning.

+ β-blockers.

5) Impact of timing of intervention on infarct size

reduction.

1/33

1) Reperfusion: a paradigm shift from mortality to HF.

Index

2) Next goal: Infarct size limitation in reperfused STEMI.

3) Ischemia/Reperfusion injury.

4) Therapies to reduce infarct size:

Reperfusion

+ Conditioning.

+ β-blockers.

5) Impact of timing of intervention on infarct size

reduction.

2/33

Adapted from Roger VL et al. Circulation 2011;123:e18-e209

STEMI: A paradigm shift

The great success of

reperfusion therapies

has resulted in a

paradigm shift in STEMI:

attention has moved from

reducing mortality

(already low) to tackling the

downstream consequences

of survival:

post-infarction heart failure.

Mortality

Heart Failure

Males

≈25%

<5%

3/33

STEMI Heart Failure

•Figure 1: Projected cumulative (2011 to 2025) economic

losses from all non-communicable diseases worldwide.

Adapted from ref 3.

•Figure 2:

4/33

1) Reperfusion: a paradigm shift from mortality to HF.

Index

2) Next goal: Infarct size limitation in reperfused STEMI.

3) Ischemia/Reperfusion injury.

4) Therapies to reduce infarct size:

Reperfusion

+ Conditioning.

+ β-blockers.

5) Impact of timing of intervention on infarct size

reduction.

5/33

Surrogate markers: predictors

Infarct size is a strong determinant of long-term mortality and chronic heart failure

6/33

Therapies to reduce MI size

Despite the

acknowledgement

of its importance,

there are no therapies

(besides reperfusion)

approved to

reduce infarct size.

Unmet clinical need!

7/33

Is all about time?M

yo

ca

rdia

l (c

ell

) d

ea

th Ischemia

Time

No reperfusion

ReperfusionJ Ross et al: J Clin Invest. 1972.

R Jennings et al: Circulation. 1977.

8/33

9/33

1) Reperfusion: a paradigm shift from mortality to HF.

Index

2) Next goal: Infarct size limitation in reperfused STEMI.

3) Ischemia/Reperfusion injury.

4) Therapies to reduce infarct size:

Reperfusion

+ Conditioning.

+ β-blockers.

5) Impact of timing of intervention on infarct size

reduction.

10/33

Ibanez, Heusch, Ovize Van de Werf.

J Am Coll Cardiol 2015;65:1454-71

Microvascular Obstruction

Myocardial Healing

: critical players

11/33

Reperfusion injury by CMR

R Fernandez-Jiménez, V Fuster, B Ibáñez, et al.: J Am Coll Cardiol 2015;65:315-23.12/33

1) Reperfusion: a paradigm shift from mortality to HF.

Index

2) Next goal: Infarct size limitation in reperfused STEMI.

3) Ischemia/Reperfusion injury.

4) Therapies to reduce infarct size:

Reperfusion

+ Conditioning.

+ β-blockers.

5) Impact of timing of intervention on infarct size

reduction.

13/33

ConditioningConditioning example of (reverse) translational research

Murry et al.: Circulation 1986;74:1124-1136

PATIENT: Clinical observation: pre-infarction angina

confers good prognosis upon infarction

BASIC RESEARCH:

Demonstration of infarct size reduction by pre-conditioning

3

J Am Coll Cardiol 2014;64:223-5

14/33

Ischemic Conditioning

Ibanez, Fuster et al.: Hurst´s the Heart 2017 (chapter 38)

LOCAL (coronary artery)or

REMOTE (peropheral organ)

15/33

RIC:

Interminent ischemia in a remote

organ DURING ongoing ischemia

in the index organ

333 patiens with first STEMI

underwent RIC protocol (4 cycles

arm cuff inflation) or regular care

CONDI trial

16/33

0

.5

1 p=0.033Sa

lvag

e In

dex

(m

edia

n [

IQR

])

PCI only rIPerC

0.55

0.75

PCI onlyrIPerC

Bøtker et al.Lancet 2010;373:727-34

Remote Ischemic Conditioning in STEMI

CONDI trial

17/33

RIC large trial

CONDI-2 trial, Denmark, Spain, Serbia.

-2,000 STEMI patients-conventional PCI vs. RIC+PCI-Combined end-point:

all-cause mortality /heart failure @ 2 years

18/33

Several trials in the pre-reperfusion era (inconclusive

results).Roberts et al, Hjalmarson et al, Yusuf et al, MILIS,..

ONE single randomized trial in the thrombolytic era.

van de Werf et al J Am Coll Cardiol 1993.

Two recent trials in the pPCI era (METOCARD-CNIC

and EARLY BAMI)Ibanez, Fuster et al Circulation 2013.

Roolvink, van´t Hof et al J Am Coll Cardiol 2016

The effect of early i.v. ß-blocker on infarct size (and

long term LV function is unclear.

SCARCE DATA IN REPERFUSED PATIENTS.

Metoprolol

19/33

Ibanez B, Fuster V et al. Circulation 2013;128:1495-1503

METOCARD-CNIC: infarct size

i.v. metoprolol before pPCI infarct size

25%

20/33

G Pizarro, V Fuster, B Ibanez et al. J Am Coll Cardiol 2014; 63: 2356-62.

METOCARD-CNIC: long-term LVEFMean LVEF (6 mo CMR):

48.7±9% vs. 45.0±11%

N=101 N=101

21/33

G Pizarro, V Fuster, B Ibanez et al. J Am Coll Cardiol 2014; 63: 2356-62.

METOCARD-CNIC: long-term events

22/33

Metoprolol reduces MVO, even normalizing to infarct size.

Microvascular Obstruction

García-Prieto et al (Submitted)23/33

Neutral study (2016)

24/33

1) Reperfusion: a paradigm shift from mortality to HF.

Index

2) Next goal: Infarct size limitation in reperfused STEMI.

3) Ischemia/Reperfusion injury.

4) Therapies to reduce infarct size:

Reperfusion

+ Conditioning.

+ β-blockers.

5) Impact of timing of intervention on infarct size

reduction.

25/33

Window metoprolol administration in METOCARD-CNIC

STEMI diagnosisReperfusion

Arterial access

Timing of metoprolol admin

Median

(53min)26/33

The longer the “on board” metoprolol duration at reperfusion, the higher the

cardioprotection

Timing of metoprolol admin

Garcia-Ruiz et al J Am Coll Cardiol 2016;67:2093-10427/33

LV

EF

(%

)

Timing of metoprolol admin

Garcia-Ruiz et al J Am Coll Cardiol 2016;67:2093-10428/33

Window β-blk admin in trials

STEMI diagnosisPCI (reperfusion)

METOCARD-CNIC

(-53 min to PCI)15mg metoprolol

EARLY BAMI

(-54 & -14 min to PCI)10mg metoprolol

Lytic therapy

---- reperfusion

COMMIT

(+? min from Urokinase)

TIMI IIB

(+45 min from rtPA)

Van de Werf

(immed before rtPA)10mg atenolol

STEMI diagnosis

29/33

Heart. 2016 Feb 24. pii: heartjnl-2015-308980.

Timing of RIC initiation

pPCI alone

RIC+pPCI

30/33

Events-powered trial

1250 anterior STEMI patients, <6 hr from symptons onset, undergoing pPCI,

Metoprolol (15mg) vs. Placebo out-of-hospital setting (long before reperfusion)

Primary outcome (win ratio approach):

CV death

HF readmission

ICD implant

LVEF <35% on 6 months CMR

Median follow-up 3 years

PIs: B Ibanez / V Fuster

31/33

1) Timely reperfusion widespread use has resulted in a massive reduction of

acute mortality during STEMI.

2) The next goal is to reduce infarct size to reduce chronic post-MI HF

3) Reperfusion injury reduction is a relevant target. Preserve microvascular

integrity!

4) Metoprolol and remote ischemic conditioning are promising therapies

5) Timing of administration of therapies to reduce infarct size seem to play a

critical role in its ability to protect from ischemia/reperfusion.

Conclusions

32/33

Acknowledgements